12-halo and 11, 12-epoxy steroids of the pregnane series



United States Patent 13 Claims. (Cl. 260239.55)

This application is a division of our parent application, Serial No. 576,259, filed April 5, 1956, now Patent No. 2,963,495, and a continuation-impart of our parent application Serial No. 519,682, filed July 1, 1955.

This invention relates to the synthesis of valuable steroids; and it has for its object the provision of (I) an advantageous process of preparing steroids of the pregn'ane (including the allopregnane, pregnene and pregnadiene) series having a l2a-halogen substituent and an ll-keto or llfl-hydroxy substituent, and of (II) certain steroids useful themselves as physiologically active steroids or as intermediates in the preparation of said physiologically active steroids.

The process of this invention essentially comprises: (a) converting a 3fl-acyloxy-11B,12;3epoxy-5a,22 (either a or b)-spirostane to the corresponding l2a-halo-11fl-hydroxy derivative; (b) oxidizing said derivative to the 12ahalo-ll-keto derivative; (0) opening the F-ring to produce a 12a-halo-A -furostene-1l-one-3fi,26-diol 3,26 diacylate; (d) opening the E ring to produce a 12a-haloallopregnane-l1,20-dione-3fi,l6fl-diol 3 acylate, 16 (4- methyl-S acyloxy)pentanoate; (e) convening said allopregnane to a IZa-halO-flllOPIegnallC-16a,17a-OXidO-11,20- dione-3fl-ol S-acylate either directly or through the 120;- halo-A -allcpregnene-l1,20-dione-3B-ol 3-acylate derivative; (f) converting said epoxide to a 12a-halo-16fi-iodo (or bromo)-a1lopregnane-11,20-dione-3B,17a-diol 3-acylate derivative; and (g) dehalogenating the latter to the corresponding l2a-halo-allopregnane-1 1,20 dione 3,8, l7a-di0l 3-acylate derivative.

The resultant 12a-halo-allopregnane-l1,20-dione 3,6, 17a-di01 3-acylate can then be saponified to the corresponding l2a-halo-allopregnane-l1,20-dione-3p,17 diol, which in turn can either be converted to the corresponding 12a-halo-3,20-diketo-17a-hydroxy-llfi-hydroxy (or 11- keto)-steroids of the pregnene series (for example: 1241- haloA -pregnene-l7a-ol-3,l 1,20-trione; 12a-halo-A -pregnene-l 1/3,17a-diol-3,20-dione; IZa-haIo-A -pregnadiene- 1711-01-3, l 1,20-trione; and IZa-haIo-A pregnadiene-I 1B, 17a-diol-3,20-dione) or to the corresponding 12a-halo-3, 20-diketo-17a,21-dihydroxy-l lfl-hydroxy (or 1 1-keto)-steroids of the pregnene series or Zl-esters thereof [e.g., 12ahalo-M-pregnene-17a,2l-diol-3,11,20 trione and esters thereof (particularly esters with hydrocarbon carboxylic acids of less than ten carbon atoms as exemplified -by acetic and benzoic acid esters), l2a-halo-A -pregnene-1119,170, 21-triol-3,20-dione and 21-esters thereof, 12a-halo-A pregnadiene-l7a,21-diol-3,l1,20-trione and esters thereof, and 12a-halo-A -*-pregnadiene-l 1B, 1 711,2 1 -triol-3,20-dione and esters thereof]. This series of conversions is effected by oxidizing the l2a-halo-allopregnane-l1,20-dione 3B, 17a-diol [after treatment with bromine to form the corresponding 12a-halo-2l-bromo-allopregnane-l1,20 dione- 3fl,17oz-di0l derivative and converting the latter with an alkali salt of an organic acid to the corresponding 12ahalo-allopregnane-ll,20-dione-3B,l7a,2l-triol 21 acylate derivative if a 2l-hydroxy steroid is desired] to the corre- 3,047,567. lratented July 31, 1962 "ice sponding l2a-halo-allopregnane-3,l1,20-trione-17a-ol, and thence to a 2a,4a-dibromo-12a-halo-allopregnane-17a-ol- 3,11,20-trione by treatment with bromine. The dibromide can then either be converted directly to a 12a-halo-A pregnadiene-l7a-ol-3,l1,20-trione by means of a tertiary base (e.g., collidine) or to a l2a-halo-A -pregnene-l7a-ol- 3,11,20-trione via the 2a-iodo-l2a-halo-A -pregnene-l7aol-3,11,20-trione intermediate. To convert the resultant ll-keto steroid to the corresponding llfl-hydroxy derivative, two different series of reactions are possible. First, the l2a-halo-3,11,20-triketo-17a-hydroxy steroid can be reacted with a semicarbazide to give the 11-keto-3,20-disemicarbazone, thence to the 1lB-hydroxy-3,20-disemicarbazone by means of an alkali metal boron tetrahydride and finally to the llfi-hydroxy-3,20-diketone by reaction with nitrous acid; or second, the 12a-halo-3,l1,20-triketol7a-hydroxy steroid can be converted to the 3,20-diketalll-ketone derivative, treated with alkali metal boron tetrahydride to form the 3,20-diketal-llfi-hydroxy derivative and then hydrolyzed to yield the l1fl-hydroxy-3,20-diketone.

The 3,20-diketal-1lfi-hydroxy serves the additional function of being an intermediate for the preparation of 12a-halo-11fl-hydroxy (or ll-keto) derivatives generally, since this intermediate upon reaction with a base yields the llfi,l2fl-epoxide-3,20-diketa1 which can be hydrolyzed by means of a dilute acid to the 11B,12fi-epoxide-3,20-diketone, which in turn can be treated in the usual manner with a hydrohalic acid to form the 12a-halo-llB-hydroxy derivative (which can, if desired, be oxidized to the halo-1 l-keto derivative).

The compounds of this invention comprises: (A) 12afluoro-5a-spirostane-3fl,llfl-diol 3-acylate (preferably the esters thereof with hydrocarbon carboxylic acids having less than ten carbon atoms as exemplified by the acetate and benzoate); (B) IZa-halo (preferably chloro or fluoro)-5a-spirostane-3fi-ol-ll-one 3 acylate; (C) 12a halo (preferably chloro or fluoro) -A -furostene-3B,

26-diol-1l-one 3,26-diacylate; (D) 12a-halo (preferablyca r wherein the 1,2 and 4,5 positions are either saturated or double-bonded, R is hydrogen, R is hydroxy or acyloxy (preferably an ester of a hydrocarbon carboxylic acid having less than ten carbon atoms), or together R and R is keto, ketal (preferably either a ketal of a lower alkanol or a lower alkanediol), or semicarbazone [it being understood that if R and R' is ketal, the double bond, if any, in the 4,5-position shifts to the 5,6- position], R" is hydrogen, R'" is fl-hydroxy, or together R" and R'" is keto; X is a-halo; Y is hydrogen, bromine, hydroxy or acyloxy (preferably an ester of a hydrocarbon carboxylic acid having less than ten carbon atoms), and Z is keto, ketal (preferably either a ketal of a lower alkanol or a lower alkane- 3 die!) or semioarbazone; (-I) 2a,4a-dibromo-l2a-halo steroids of the general formula wherein X is u-halo (preferably chloro or fluoro) and Y is hydrogen, hydroxy or acyloxy (preferably an ester of a hydrocarbon earboxylic acid having less than ten car- 10 of the compound. The 12u-bromo-1l-keto-steroids are of further use as intermediates in the preparation of the corresponding l2-debromo derivatives, to ,which they are converted by treatment with either zinc dust in acetic acid or chromous chloride.

bon atom); (I) 2a-iodo-l2a-halo steroids of the general 15 For a clearer understanding of the foregoing general formula and following detailed description of the processes of this invention, reference is made to the following schematic analysis, wherein the capital letters designate the general class of compounds and the Roman numerals the specific 20 embodiments thereof of the examples:

wherein X and Y are as hereinbefore defined; and (K) 1lp,l2p-epoxy steroids of the general formula K01 pyridine a r-A cnco III 'x-chA- flq ci co IV x-mn-ca do wherein the 1,2 and 4,5-positions are either saturated or as double-bonded (preferably the 1,2-position is saturated and the 4,5-position is double-bonded), and Z is keto or ketal (preferably either a ketal of a lower alkanol or a lower alkanediol) [it being understood that if R and R is ketal, the double bond, if any, in the 4,5-position shifts to the C 5,6-position], and Y is as hereinbefore defined.

v df-Ch A-CHG) I X-Cl; k-GHCO The final products of this invention [Compounds H, Y: x A 1 3 x A g wherein the 4,5-position is double-bonded and Z and H202. Ex. NaOl-l A0 A0 A0 Egan: v to xxxv collidine lL to mm mm: i 01; Y co m coo Eli-0:; "I XXV X-F; Y: i=1; Y:

m: X=Cl;Y'- xxx xzcnvuu a m: x r; Y'.-.H xxvn g: r; Y

H XXXV X RY' HXXXIK X-F;Y -H XLIII X FBY' H Compounds Hcontaining oxo radicals in the 3- and 11- positions can then be converted to the corresponding llprivative having a different halogen substituent in the 120:- hydroxy derivatives or to an ll-keto or llp-hydroxy deposition by the following series of steps:

OH a-saturated; ,5-

double bonded) 11 an H1.

(1,2-saturated; 5,

double-bonded) (1,2-saturated; 5,6-

double-bonded) XLVII Y' I OH (1,2-saturated;

t,5-doub1e-oonded) XLVIII Y' I CH COO (1,2-saturated;

t,5-double-bonded) To prepare the steroids of this invention, SB-acyloxyl1,6,l2fl-epoxy-5a-spirostane (e.g., 3fl-acetoxy-llfl,l2pepoxy-5a,22a-spirostane) is treated with a hydrohalic acid (preferably either hydrochloric or hydrofluoric acid) in the usual manner to yield the corresponding 12a-halo (preferably chloro or fluoro)-l1B-hydroXy-Bfl-acyloXy-Saspirostane, Compounds A [e.g., 12a-Chl0l'0-5a,22a-Spirostane-3p,11B-diol 3-acetate, Compound II, and 12afluoro-5a,22a-spirostane-3fl,1lp-diol S-acetate, Compound I]. pend, of course, on the particular ester derivative of the epoxyspirostane initially chosen, and since the sole function of this ester group is to protect the 3fl-hydroxyl radical, any acid is utilizable. Because of their availability, however, the preferred acids are those of hydrocarbon carboxylic acids containing less than ten carbon atoms and include the lower alkanoic acids (e.g., acetic, propionic, and enanthic acids), the aromatic acids (e.g., benzoic, toluic and xyloic acids), the cycloalkanoic acids (e.g., cyclohexanecarboxylic acid), and the aralkanoic acids (e.g., phcnylacetic and phenylpropionic acid).

Compounds A are then oxidized, as by treatment with chromic oxide, to the corresponding l2m-halo-11-keto-3flacyIoXy-Sa-Spirostane derivative, Compounds B [e.g., 12achloro 511,220; spirostane ol 11 one 3 acetate, Compound III, and 1Zea-fluoro-5a,22a-spirostane-3,8-ol-11- one 3-acetate, Compound IV]. This reaction is preferably conducted in an inert organic solvent (e.g., acetone).

Compounds B are then heated under substantially anhydrous conditions, preferably in an organic solvent comprising an acid anhydride and a Lewis acid, e.g., pyridine hydrochloride, to open the F ring, thereby yielding the corresponding 12a halo ll keto 3p acyloxy A* -furostene-26-ol 26-acylate derivative, Compounds C, wherein the 26-acyl radical corresponds to the acyl radical of the acid anhydride employed in the reaction. Examples of such furostene derivatives include 120'.- chloro-A -furostene-3fi,26-diol-ll-one 3,26-diacetate, Compound V, and l2a-fluoro-A -furostene-3B,26-diol- The esterifying radical in the 3-position will de-- cn y XLIX X-CliY- (1,2-saturated; t, 5-double-bonded) X Br; Y CH (100 (1,2-sat; rated; '4, 5-double-bonded) diol-ll,20-dione 3-acetate, tanoate, Compound VII, and l2a-fluoro-allopregnanepreferably efiected by refluxing the spirostane and pyridine hydrochloride in acetic anhydride under anhydrous conditions.

Compounds C are then oxidized either by means of a peracid (e.g., peracetic acid formed in situ by means of acetic acid and hydrogen peroxide) or chromic acid to yield the corresponding IZa-halo-ll-keto-3B-acyloxy-allopregnane-l6fl-ol-20-one 16-(4-methyl-5-acyloxy)pentanoate, Compounds D [e.g., l2a-chloro-allopregnanc-3fl,16p- 16-(4-methyl-5-acetoxy)pen- 3fl,16p-diol-11,20-dione 3-acetate, l6-(4-methyl-5-acetoxy)-pentanoate, Compound VIII].

Compounds D can then either be dehydrated by treatment with a base (e.g., potassium hydroxide) to the corresponding l2a-halo-11-keto-3B-acyloxy-A"-allopregnene- 20-one, Compounds E (e.g., 12a-chloro-A -allopregnene- 3fl-ol-l1,20-dione 3-acetate, Compound IX, or 12a-fluoro- A -allopregnene-3fl-ol-1l,20-dione 3-acetate, Compound X), and thence by treatment of the resultant Compounds E with hydrogen peroxide and an alkali hydroxide or carbonate to the corresponding 12a-halo-1l-keto-3B-acyloxy-allopregnane-l6u,l7a-oxido-20-one, Compounds F (e.g., 1Za-chloro-allopregnane-16a,l7a-oxido-3fl-ol-11,20- dione 3-acetate, Compound XI, or 12a-tluoro-allopregnane-l6a,17a-oxido-3 fl-ol-l 1,20-dione 3-acetate, Compound XII) or directly to Compounds F by treatment of Compounds D with hydrogen peroxide in a basic medium (e.g., methanolic sodium hydroxide).

Compounds F are then hydrohalogenated by treatment with either hydrobromic or hydroiodic acid to yield the corresponding 12a-halo-16B-bromo (or iodo)-1l-keto-3fiacyloxy-allopregnane-l7a-ol-20-one derivatives, Compounds G (e.g., 12a-chloro-16p-bromo-allopregnane- 3fi,l7a-diol-ll,20-dione 3-acetate, Compound XIII, 12achloro-l 6fl-iodo-allopregnane-3B,l7a-diol-l 1,20-dione 3- acetate, Compound XIV, and l2a-tluoro-l6B-iodo-allopregnane 3fl,17a-diol-l1,20-dione 3-acetate, Compound XV ll-one 3,26-diacetate, Compound VI. The reaction is Compounds G are then dehalogenated in the l6-posi- 12a-fluoro-allopregnane- 17 u-l-3,1 1,20-trione,

- with an acid (e.g., perchloric acid) or base (e.g., potassium carbonate) in a lower alcohol to yield the corresponding 12a-halo-allopregnane-3p,17a-diol-11,20-dione, Compounds Hb (e.g., 'l2a-chloro-allopregnane-3p,17adiol-11,20-dione, Compound XVIII, and 12a-fluoro-allopregnane-IiflJh-diol-l1,20-dione, Compound XIX).

If a 21-hydroxy steroid is desired, Compounds Hb are then brominated in the 21-position by treatment with bromine in an inert organic solvent to yield the corresponding 12u-halo-2l-bromo-allopregnane-3fl,17a-diol-11,

20-dione, Compounds Hc (e.g., 12a-chloro-2l-bromo-allopregnane-3fi,17a-diol-ll-20-dione, Compound XX, and 12a fluoro 21 bromo allopregnane 3fi,l7 diol 11,20-dione, Compound XXI) in which the 2l-bromine atom is then replaced by an acyloxy group by means of an alkali salt of an organic acid, preferably acetic acid, whereby the resultant 2l-substituent is an ester of the acid employed, to yield the corresponding 12a-halo-21- acyloxy allopregnane 319,170: diol 11,20 dione, Compounds Hd (e.g., 12a-chloro-allopregnane-3p,1711,21- triol-l1,20-dione ZI-acetate, Compound XXII, and 12afluoro-allopregnane-Bfi,17a,21-triol-11,20-dione 21-acetate, Compound XXIII), which may then be hydrolized, if desired, to yield the free 21-hydroxyl derivatives.

Compounds Hd or Compounds Hb (if a 21-unsubstituted steroid is desired) are then oxidized by treatment with chromic acid to yield the corresponding 12a-halo- 3,11-diketo-allopregnane, Compounds He (e.g., 12achloro-allopregnane-17a,2l-diol-3,11,20-trione 21-acetate, Compound XXIV, 1Za-fluoro-allopregnane-17a,21-diol-3, 11,20-trione 21-acetate, Compound XXV, 12a-chloro-allopregnane-17a-ol-3,11,20-trione, Compound XXVI, and Compound 70(VH).

To introduce a double-bond in the 4,5-position, Compounds He are treated with at least two moles of bromine per mole of steroid, whereby 12a-halo-2a,4a-dibromoallopregnane derivatives, Compounds I are formed (e.g., 12a chloro 211,40: dibromo allopregnane 1701,21- diol-3,1'1,20-trione 21-acetate, Com-pound XXVIII, 12afluoro 2a,4a dibromo allopregnane 1711,21 diol- 3,l1,20-trione 2l-acetate, Compound XXIX, 12a-chloro- 2a,4-dibromo-allopregnane-17a-ol-3,11,20-trione, Compound XXX, and 12a-fluoro-2a,4a-dibromo-allopregnane- 17m-ol-3,1l,20-trione, Compound XXXI).

To prepare the corresponding A -pregnane, Compounds I are heated with an iodide salt (e.g., sodium iodide) whereby the corresponding 1Za-halo-Za-iodo-M-pregnane derivative, Compounds I, are formed (e.g., IZa-ChiOrO-Zmiodo-cortisone 21-acetate, Compound XXXII, IZa-fiuoro- Za-iOdO-OOI'USOIIQ 21-acetate, Compound XXXIII, 12- chloro 2a iodo 11 keto 17a hydroxyprogesterone, Compound XXXIV, and IZa-flllOlO-Za-iOdO-l 1-keto-l7ahydroxyprogesterone, Compound XXXV), and the iodo radical is removed by reaction with a reducing agent such as aqueous chromous chloride to yield Compounds Hf (e.g., 12a chloro cortisone 21 acetate, Compound XXXVI, 12a fluoro cortisone 21 acetate, Compound XXXVII, 12a chloro-l l-keto-17 a-hydroxyprogesterone, Compound XXXVIII, and 12u-fluoro-1l-keto-17a-hydroxyprogesterone, Compound XXXIX).

To obtain a A -pregnadiene derivative, Compounds I are heated with collidine to yield the corresponding A pregnadiene derivative, Compounds Hg (e.g., l2a-chloro- A pregnadiene 1711,21 diol 3,11,20 trione 21 acetate, Compound XL, 12a-fluoro-A -pregnadiene-1711,21- diol 3,11,20 trione 21 acetate, Compound XLI, 12achloro-A -pregnadiene-17a-ol-3,l1,20-trione, Compound XLII, and 1Za-Huoro-A- -pregnadiene-17a l-3,11,20-trione, Compound XLIII). I

Compounds Hf and Hg, containing a 21-acyloxy radical can be hydrolyzed in the usual manner, as by the use of a salt of a strong base and a weak acid (e.g., potassium carbonate) to yield the free 21-hydroxyl derivative (e.g., 12m-chlorocortisone, 12a-fluorocortisone, l2a-chloro-A pregnadiene-.17a,21-diol-3,11,20-trione and l2a-fiuoro- A -pregnadiene-17a,21-diol-3,1 1,20-trione) Compounds He, Hf, and Hg can further be converted to the corresponding llp-hydroxy derivatives by either of two processes. In the first process, the steroid is treated with semicar-bazide in a lower alcohol to yield the 3,20- disemicarbazone, Compounds Hh, which are then treated with an alkali metal boron or lithium tetrahydride (e.g., potassium boron tetrahydride) in an organic solvent inert towards the tetrahydride (either in the presence or absence of water) to yield the corresponding llfi-hydroxy derivative, Compounds Hi, and the resultant steroids are then reacted with nitrous acid in a dilute mineral acid (e.g., hydrochloric acid) to yield Compounds H, having an llp-hydroxy radical, the 12a-halo radical of the starting steroid and keto groups in the 3,20-positions (e.g., 12a-chlorohydrocortisone, 12a-fluoroh"drocortisone, 12achloro-l 1p,17a-dihydroxy-progesterone, l2a-fiuoro-1 1B, l7a-dihydroxy-progesterone, 1Za-chloro-A -pregnadiene- 1 1B,17a,21-triol-3,20-dione, 1Za-fluoro-A -pregnadiene- 1 1p, 170:,2 l-triol-3,20-dione, l2a-chloro-A -pregnadiene- 1 1,9,17u-diol-3,20-dione, 12a-fluoro-A -pregnadiene-l 1p, 17a-diol-3,20-di0ne, 12a-chlor0-allopregnane-11p,l7a',2ltriol-3,20-dione, l2a-fiuoro-allopregnane-l l,B,l7ot,21-triol- 3,20 drone, 1211 chloro allopregnane 115,1"1 diol- 3,20-dione and 12a-fluoro-allopregnane11fl,17a-orol-3,20- dione).

In the second process, Compounds Hf or Hg are first hydroly zed and then ketalized by treatment with a 1,2- glycol (e.g., ethylene glycol) in an inert solvent in the presence of an acid catalyst, to form the corresponding 3,20-diketal derivatives, Compounds Hj, which are then reduced with an alkali metal boron or lithium tetrahydride, as described hereinbefore, to yield the 11 fl-hydroxy 3,20-diketal derivative, Compounds Hk. The latter are then either treated with a dilute acid, such as sulfuric acid in methanol, to yield a 12a-ha1o-1lfl-hydroxy-3,20-diketo steroid wherein the halo group is that of the starting steroid, or dehydroch-lorinated (when the l2a-halo substituent is chlorine) to the corresponding 1lfi,12fl-epoxide,

Compounds Ka, by treatment with a salt of a strong base and a weak acid (e.g., potassium carbonate). The resultant epoxide ketalized in the 3,20-positions, is then hydrolyzed with dilute acid (e.g., sulfuric acid) to yield the corresponding 11B,12fl-epoxy-3,20-diketo derivative, Compounds Kb, which can be treated with a hydrohalic acid (e.g., hydrofluoric, hydrochloric, hydrobromic, or hydroiodic acid), preferably after esterifying any free 21- hydroxyl radical present, to yield the respective 12a-halollfl-hydroxy derivative. The resultant IZu-halo-llflhydroxy steroid, can, if desired, be oxidized with chromic acid to its 12a-halo-11-keto derivative, thereby affording a generalized method for producing any 12a-halo-l1-keto derivative.

The following examples are illustrative of the invention (all temperatures being in ccntigrade):

EXAMPLE 1 Into a solution of 2 g. of llfl,12B-epoxy-5a,22aspirostane-3fl-ol B-acetate in 76 ml. of chloroform and 4 ml. of absolute alcohol is passed with stirring at 0 a stream of hydrogen fluoride. After 10 minutes two layers form and the addition of hydrogen fluoride is terminated. After minu-tesat 0", the reaction mixtureis neutralized with a suspension of sodium bicarbonate in water and the layers separated. The chloroform is washed with water, dried over sodium sulfate and evaporated to dryness in 1 1 vacuo. The crystalline residue upon one crystallization from chloroform-alcohol furnishes pure 9a-'flu0I'O-5az,22aspirostane, 313,128 diol 3 acetate having the following properties: M.P. about 251-252; [0.] --70 (c. 0.96 in chloroform),

Analysis-Cale. for C H O F (492.65): C, 70.69; H, 9.21; F, 3.85. Found: C, 70.66; H, 9.02; F, 3.91.

[The IZfl-acetate of 9a-fluoro-5u,22a-spirostane-3p, 12,8-diol S-acetate can be prepared by allowing a solution of 25 mg. of the compound in 0.5 ml. of pyridine and 0.5 ml. of acetic anhydride to remain at room temperature for 18 hours, and removing the reagents to yield a crystalline residue consisting of the 12,9-acetate, which after recrystallization from 95% ethanol has the following properties: M.P. about 257-258; [0.], 75 (c. 0.98 in chloroform) Analysis.Calc. for C H O F (534.66): C, 69.64; H, 8.86. Found: C, 69.76; H, 8.61.

The mother liquors of the above reaction with hydrogen fluoride are combined and dissolved in 10 ml. of benzene and 20 ml. of hexane. After centrifuging off a small flocculent precipitate, the resulting solution is chromatographed on 15 g. of sulfuric acid-washed alumina. Elution of the column with 700 ml. of a mixture of one part of benzene and two parts of hexane furnishes after recrystallization from 95 ethanol, pure l2a-fl110r0- 5a,22a-spirostane-3,S-1lfl-diol 3-acetate having the following properties: M.P. about 239-241; [a] -44 (c. 0.65 in chloroform);

Analysis-Cale. for C H O F (492.65); C, 70.69; H, 9.21. Found: C, 70.67; H, 9.11.

EXAMPLE 2 A solution of 3.43 g. of 3,3-acetoxy-12a-chloro-5u,22aspirostane-llfl-ol (II) (see J. Schmidlin and A. Wettstein, Helv., 36, 1241 (1953)) in 340 ml. of reagent grade acetone is oxidized dropwise, with stirring at room temperature with 4.1 ml. of C10,, solution (excess, calc. amount 2.4 ml. solution containing 200 mg. Cr and 320 mg. conc. H3804 in' 1 ml. water). The excess CrO is destroyed by addition of 1 ml. of ethanol and after addition of 100 ml. of water, the solution is decanted from remaining salts, concentrated in vacuo until most of the acetone is removed and the resulting crystals filtered off. Yield about 2.87 g. (84%), M.P. about 173-176". The analytical sample is recrystallized several times from ethanol and has the following properties: M.P. about 183-185, [ab-80 (c. 0.44 in chloroform),

22;? 5.75,., 5.78,. (doublet), 5.85,.

EXAMPLE 3 I 2u-FIuoro-5 a,22a-Spir0stane-3,8-0l-1 1 -One 3-Acetate (IV) To a solution of 60 mg. of l2a-fluoro-5a,22a-spirostane-3,8,l1fl-dio] 3-acetate (I) in 6 ml. of reagent grade acetone is added at room temperature 0.08 ml. of .a solution of chromic acid (200 mg.) and sulfuric acid (320 mg.) in water (1 ml.). After 55 hour 0.25 ml. of alcohol and minutes later 5 ml. of water is added and the acetone removed in vacuo. The residue is taken up in chloroform and the resulting CHCl -extract washed with water, dilute bicarbonate and again with water. Removal of the solvent from the sodium sulfate-dried extract furnishes the crude ll-ketone, which after crystallization from alcohol has the following properties: M.P. about 203-204; [d -6 (c. 1.28 inCHCI an: 5.79,., 5.82,. (shoulder) Analysis.-Calcd. for C H O F (490.63): C, 70.99; H, 8.83. Found: C, 71.13; H, 8.66.

. EXAMPLE 4 I Za-Ch Zora-A -Furostene-3,9,26-Diol-I 1 -One 3,26-Di-A cetate (V) A solution of 4.45 g. of the l2u-chloro-ll-keto-spirostane (III) prepared in Example 2 and 2 g. of pyridine hydrochloride in 23 ml. of acetic anhydride is refluxed under exclusion of moisture for 5 hours. The mixture is then cooled in an icebath and the acetic anhydride destroyed by careful addition of ice. The mixture is extracted with ethyl acetate, the ethyl acetate extract washed free of acetic acid and pyridine, dried over sodium sulfate and evaporated in vacuo. A yield of about 4.84 g. of the crude furostene diacetate (V) is obtained. Several recrystallizations from ethyl acetate yield the analytical sample, M.P. about 118119; [a] +7 (c. 0.4 in chloroform);

Nuld Analysis.-Calcd. for C31H4508Cl (549.13): C, 67.80; H, 8.26; Cl, 6.46. Found: C, 67.88; H, 8.09; Cl, 6.10.

Similarly, by substituting 12a-fiuoro-5a,22a-spirostane- 3,9-ol-11-one S-acetate (IV) for the 12a-chlorospirostane in the procedure of Example 4, 12a-fluoro-A= -fi1rostene-3fi-26-diol-11-one 3,26-diacetate (V1) is produced.

EXAMPLE 5 JZa-Chloro-A lIopregnane-3 13,16,8-Diol-11,20-Di0ne 3- A cetate, 1 6 -(4-M ethyl-5 -A cetoxy )Pentanoate VII) A no specific U.V. absorption; k512i? 5.75,., 5.80,., 5.85,.

max.

Analysis.Calcd. for C -H O Cl (581.13): C, 63.92; H, 7.81. Found: C, 63.56; H, 7.57.

(b) By oxidation with chromic acid.-To a solution of mg. of the spirostane diacetate (V) in a mixture of 2 ml. of ethylene dichloride, 2 ml. of glacial acetic acid and 0.4 ml. of water is added with stirring at 10 over a 30-minute period 2 ml. of a solution of chromic acid in acetic acid (25 mg./ml.). The reaction mixture is allowed to warm up to and remain at room temperature for an additional two hours. Excess chromium trioxide .is destroyed by the addition of 0.5 ml. of alcohol and the reaction mixture concentrated in vacuo. The residue is distributed between chloroform and water and the chloroform solution washed with water, sodium bicarbonate and again with water. Evaporation of the sodium sulfate-dried extract to dryness furnishes a crystalline residue, which after recrystallization from alcohol affords about 50 mg. of the allopregnane derivative VII, M.P. about 188190.

Similarly, by substituting l2a-fluoro-A -furostene- 3,9,26-diol-ll-one 3,26-diacetate (V) for the 12a-chlorofurostene, 12a-fluoro-allopregnane 3fi,l6p-diol-ll,20-dione 3-acetate, 16-(4-methyl-5-acetoxy)-pentanoate (VIH) is formed.

13 EXAMPLE 6 12a-Chl0ro-A -Allopregnene-3B-0l-IL20- Dione 3-Acetate (IX) To a solution of the allopregnane derivative (VII) in 4 ml. of tertiary butanol is added a solution of 200 mg. of KOH in 0.3 ml. of water. The mixture is allowed to remain at room temperature for 1.5 hours and then neutralized with dilute hydrochloric acid. Water is added and the mixture extracted with ether. tract is dried over sodium sulfate and the solvent removed in vacuo. The residue is reacetylated with 1 ml. of pyridine and 1 ml. acetic anhydride for 18 hours and after removal of the reagents in vacuo dissolved in 5 ml. of benzene and 5 ml. of hexane for chromatography on 3 g. of sulfuric-acid washed alumina. Elution of the column with benzene-hexane 1:1 furnishes in the first 200 ml. the desired A -allopregnene derivative (IX), which after crystallization from ether hexane has the following properties: M.P. about 202-204"; [a] +3 (c. 0.32 in chloroform),

RES? 229m (e=11,000), $395.76 5.85p, 6.03p, 6.29;;

AnaZysisJ-Calcd. for C H O CI (406.94): C, 67.88; H, 7.68. Found: C, 67.77; H, 7.60.

In the same manner, by substituting 12u-fluoro-allopregnane-3fl,16p-diol-1 1,20-dione 3-acetate, 16- (4-methyl- S-acetoxy) pentanoate (VIII) for the chloro compound in the procedure of Example 6, l2a-fluoro-A -allopregnene-3B-ol-ll,20-dione 3-acetate (X) is formed.

EXAMPLE 7 12a-Chloro-All0pregnane-I6a,1 7a-0xid0-3fi-0l- 11,20-Dine 3-Acetate (XI) To a solution of 100 mg. of l2a-chloro-A -allopregnene-3fi-ol-ll,20-dione B-acetate (IX) in 8 ml. of cold methanol, 0.9 ml. of cold 30% H 0, and 0.37 ml. of 4 N NaOH is added. The mixture is allowed to remain at 0 for 6 hours and then diluted with water and neutralized with dilute hydrochloric acid. Chloroform is added and the resulting chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue is acetylated with 1 ml. of acetic anhydride and 1 m1. of pyridine for 15 hours and after removal of the reagents in vacuo, recrystallized from 95% alcohol. The resulting 16,17-epoxide has the properties described in the following Example 8.

Similarly, by substituting l2u-fluoro-A -allopregnene- 3p-ol-11,20-dione 3-acetate (X) for the chloro steroid of Example 7, l2a-fluoro-allopregnane-l6a,17a-oxido-3fiol-ll,20-dione 3-acetate (XII) is formed.

Compounds XI and XII can also be prepared directly from Compounds VII and VIII, respectively, as illustrated by the following example:

EXAMPLE 8 1.93 g. of VII is suspended in 157 ml. of cold methanol and 17.3 ml. of cold 30% H 0, and 7.8 ml. of cold 4 N NaOH are added. The mixture is stirred with cooling in an icebath for 6 hours, then about 50 ml. water is slowly added and the mixture filtered quickly, and washed with dilute acetic acid and water until neutral. The crude epoxide (XI) melts at about 272-275 (yield approximately 847 mg). The mother liquor is extracted with chloroform, the chloroform extract washed free of hydrogen peroxide and acetic acid with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue after reacetylation with 2 ml. of pyridine and 2ml. of acetic anhydride furnishes an additional 330 mg. of XI after crystallization of the crude acetylation residue from ethanol.

The analytical sample obtained by recrystallization from 95% alcohol has the following properties: M.P. about 278-80, [ah -6 (c. 0.21 in chloroform),

The ether ex- 10 Analysis.-Calcd. for C H O Cl (422.94): C, 65.31; C, 65.31; H, 7.30. Found: C, 65.30; H, 7.44.

EXAMPLE 9 1 Zu-Ch lam-1 6fl-Bromo-A llopregnane-3p,1 7a-Di0l- 11,20-Di0ne S-Acetate (XIII) To a solution of mg. of the 16a,l7a-epoxide (XI) in 3 ml. of glacial acetic acid is added 1 ml. of 7% HBr in acetic acid (1 part of 48% aqueous HBr plus 6 parts of glacial acetic acid). The reaction mixture is allowed to stand at room temperature over night, poured on ice and extracted with chloroform. The chloroform extract is washed with water, sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about 103 mg.) after recrystallization from acetone-hexane furnishes the pure bromohydrin of the following properties: M.P. about 219-220, [ah -37 (c. 0.4 in chloroform);

Analyris.-Calcd. for C,,H,,0,C1Br (503.87): C, 54.82; H, 6.40. Found: C, 54.22; H, 6.27.

EXAMPLE 10 I 2a-ChIor0-16p-Iado-A llopregnane-3fl,1 7a-Di0l- 11,20-Dione 3-Acetate (XIV) To a solution of 400 mg. of 12m-chloro-16a,l7a-epoxyallopregnane-Bp-ol-l1,20-dione 3-acetate (XI) in 20 ml. of glacial acetic acid is added under a carbon dioxide blanket 3 ml. of 'redistilled iodine-free 57% hydriodic acid. The mixture is allowed to stand in the dark for 40 hours, diluted with water and extracted with chloroform. The chloroform extract is washed with water, sodium bicarbonate solution and again with water containing a small amount of sodium sulfite. The chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about 547 mg.) crystallizes readily from alcohol and is used in the next step without further purification. An analytical sample after recrystallization from alcohol has the following properties: M.P. about 188l90 (dec.), [ah -14 (c. 0.66 in chloroform);

Analysis.-Calcd. for C H =0 Cl (552.8): C, 49.96; H, 6.19. Found: C, 50.27; H, 6.11.

Similarly, by substituting l2a-fluoro-allopregnane-l6a, 17a-oxido-3p-ol-l1,20-dione S-acetate (XII) for the chloro compound of Example 10, 12a-fluoro-16fl-iodoallopregnane-3p,l7a-diol-l1,20-dione 3-acetate (XV) is prepared.

EXAMPLE 11 12a-Chloro-All0pregnane-3B,I 7u-Di0l-I I ,20- Diane 3-Acetate (XVI) To a solution of 1.0 g. of the 12a-chloro-l6fl-iodide (XIV) in 50 ml. of peroxide free dioxane is added 8 ml. of neutral Raney nickel (commercial, pyrophoric) suspended in 10 ml. of dioxane and the resulting suspension shaken in the dark at room temperature for 1 hour. The catalyst is centrifuged off and the solution is diluted with water and chloroform. The chloroform-dioxane phase is separated ofl, dried over sodium sulfate and the solvents evaporated in vacuo. The crystalline residue after recrystallization from 95 alcohol furnishes pure 12achloroallopregnane-Sfl,l7a-diol-ll,20-dione 3-acetate of the following properties: M.P. about 222-224"; [011 35 (c. 0.42 in chloroform);

E22 2.87 5.79 5.82;; (shoulder), 5.87;;

. Analysis.-Calcd. for C33H33o5Cl (424.96): C, 65.16; H, 7.83; Found: C, 64.71; H, 7.44.

Similarly, by substituting l2a-fluoro-l6p-iodo-allo- EXAMPLE 12 12a-Chloro-A llbpregnane-3BJ 7 m-D 1' 01-1 1 ,20-D ione (XVIII) A221,? 2.96;, 3.05 (shoulder), 5.82 5.92;

Analysis.Calcd. for C, H Cl (382.92): C, 65.86; H, 8.16. Found: C, 65.99; H, 8.26.

Similarly, l2a-fluoro-allopregnane-3fl,17a-diol-11,20-dione 3-acetate can be hydrolyzed to the free S-hydroxyl compound (XIX).

The preparation of the 21-oxy steroids of this invention is illustrated by the following three examples:

EXAMPLE 13 12u-ChI0r0-21BrOmo-AlldpregnanedflJ 7 a- Diol-I 1.20-Di0ne (XX) To a solution of 150 mg. of 12a-chloroallopregnane- 3p,17a-diol-11,20-dione (XVIII) in 9 ml. of chloroform is added at room temperature with stirring 1.60 ml. of a solution of bromine in chloroform (43.2 mg./ml.). To initiate the reaction a drop of 10% HBr in acetic acid is added. A total reaction time of 8 minutes is required. At the end of that period water is added and the chloroform solution washed neutral with sodium bicarbonate. After drying over sodium sulfate the solvent is removed in vacuo and the residual bromo compound crystallized from acetone-hexane. Pure 12a-Ch10tO-21-b1'0m0all0- pregnane-3p,17a-diol-l1,20-dione has the following properties: M.P. about 195-l96 (dec.); [0:]; 37 (c 0.68 in CHCl Analysis.-Calcd. for C H O ClBr (461.81): C, 54.61; H, 6.54. Found: C, 55.68; H, 6.72.

Similarly 12a-fluoro-allopregnane-3p, l7a-diol-l 1,20-dione can be brominated to l2u-fluoro-21-bromo-allopregnane-Bfl, 17u-diol-1 1,20-dione (XXI) EXAMPLE 14 I2e-ChIoro-A llopregnan e-3fl,1 7a-21 Triol- I 1,20-Dione 21-Acetate (XXI) To a solution of 252 mg. of l2a-chloro-2l-bromoallopregnane-3p,17a-diol-11,20-dione (XX) in 16 ml. of acetone is added in the order given 0.35 ml. of glacial acetic acid, 558 mg. of potassium bicarbonate and 19 mg. of sodium iodide. The resulting mixture is refluxed with stirring for 17 hours, after which period water is added and the acetone removed in vacuo. Ethyl acetate is then added to the aqueous suspension and the layers separated and the ethyl acetate solution washed with sodium bicarbonate and with water. The sodium sulfate-dried ethyl acetate extract is concentrated to dryness in vacuo and the resulting crystalline residue recrystallized from 95 alcohol. The pure compound has the following properties: M.P. about 158-160"; [11],, 17 (c. 0.75 in CHCl A532 2.85 3.00;, 5.75;; (shoulder), 5.82;:

Analysis.-Calcd. for C, H 0 Cl (440.94): C, 62.64; H, 7.54. Found: C, 62.45, H, 8.02.

Similarly 12a fluoro 21 bromo allopregnane- 3p,17a-diol-11,20-dione yields l2a-fluoro-allopregnane- 3fl,17a,2l-triol-11,20-dione 21-acetate (XXIII).

EXAMPLE 15 1 lot-Ch loro-A lldpregnane-I 7u,21 -Di0l-3,I I ,20-

Trione 21 Acetate (XXIV) To a solution of 236 mg. of l2a-chloroallopregnane- 3fl,17a,21-triol-11,20-dione 21-acetate (XXII) in 24 ml. of reagent grade acetone is added dropwise with stirring at room temperature 0.67 ml. of a solution of 188 mg. of CrO and mg. of sulfuric acid in 1 ml. of water. After a total reaction time of 25 minutes the excess CrO is reduced with 0.5 ml. of alcohol and water is added. After removal of the acetone in vacuo chloroform is added, the resulting chloroform extract, washed with water, sodium bicarbonate solution, and again with water. The solution is then dried over sodium sulfate and concentrated to dryness in vacuo. Pure -12a-chloroallopregnane-l7e,2l-diol-3,l1,20-trione 21-acetate after recrystallization from acetone-hexane has the following properties: M.P. about 214-216; [11],," +4 (c. 0.83 in CHCl EXAMPLE 16 IZz-Chloro-Allopregnane-17a-Ol-3J1,ZO-Trione (XXVI) A solution of 500 mg. of 12a-chloroallopregnane-3fi, 17a-di0l-l1,20-dione (XLIII) in 50 ml. of reagent grade acetone is treated dropwise with stirring with 1.4 ml. of a solution of 188 mg. of Q0; and 300 mg. of sulfuric acid in 1 ml. of water. After a total reaction time of 40 minutes, 0.5 ml. of alcohol is added and then 20 ml. of water. After removal of the acetone in vacuo the resulting mixture is extracted with chloroform, the chloroform extract washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue upon crystallization from alcohol furnishes pure 12a-chloroallopregnane- 17a-ol-3,11,20-trione (XXVI).

Similarly l2a-fluoro-allopregnane-3fi,l7a-diol-11,20-dione (XIX) can be oxidized to l2a-fluoro-allopregnane- 17a.-ol-3,1 1,20-trione (XXVII).

EXAMPLE l7 IZa-Ch loro-2a,4a-Dibromo-A llopregnane-I 711,21- Dial-3,1 1,20-Trione 21 A cetate X X VIII To a solution of 200 mg. of l2u-chloroallopregnanel7a,2l-diol-3,ll,20trione 21-acetate (XXIV) in 13 ml. of glacial acetic acid is added at room temperature with stirring 3.35 ml. of a solution of bromine in glacial acetic acid (45.4 mg./ml.). To initiate reaction a few drops of 10% hydrogen bromide in acetic acid are added. Bromination is complete after 3 hours. The mixture is taken up in chloroform and water and the resulting chloroform extract washed with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue crystallizes readily from acetone-hexane and furnishes the pure dibromide having the following properties: M.P. about 179-l81 (dec.); +l.5 (c., 1.26 in CHCl Similarly 12a fiuoro-allopregnane-l7a,2l-diol-3,l1,20- trione 21-acetate (XXV), 12a-chloro-allopregnane-17aol-3,ll,20-trione (XXVI) and l2a-fluoro-allopregnane- 17 17u-ol-3,11,20-trione (XXVII) can be dibrominated to the respective 2a,4a-dibromo derivatives (Compounds XXIX, XXX, and XXXI').

EXAMPLE 18 1Zct-ChIOI'O-Za-IOdOCOTIiSOItE 21 -Ace'tate (XX XII A solution of 90 mg. of the dibrornide (XXVIII) prepared by the procedure of Example 17 and 240 mg. of sodium iodide in ml. of acetone is refluxed for 18.5 hours. The reaction mixture is diluted with water and the acetone removed in vacuo. The resulting suspension is extracted with chloroform and the chloroform solution washed with water containing a trace of sodium sulfite. Evaporation of the sodium sulfate-dried chloroform extract in vacuo leaves the 2-iodide as a crystalline residue, which after recrystallization from acetone-hexane melts at about 166167 (dec.);

(e=14,000). The iodide is used in the reaction of Example 19 without recrystallization.

Similarly, 12o: fluoro 2a,4a dibromo allopregnane- 17a,2l-diol-3,11,20-trione 2l-acctate (XXIX), IZa-ChlO- ro 2a,4u dibromo allopregnane 17a ol 3,11,20- trione (XXX), and l2a-fluoro-2a,4a-dibromo-allopregnane-17a-ol-3,l1,20-trione (XXXI) can be converted to l2a-iluoro-2a-iodocortisone 21-acetate (XXXIII), 12- chloro 2a iodo 17a hydroxy 11 ketoprogesterone (XXXIV), and 12a-fluoro-2a-iodo-l7a-hydroxy-1l-ketoprogesterone (XXXV) respectively.

EXAMPLE 19 IZa-Chlorocortisone ZI-Acetate (XXXVI) To a solution of 50 mg. of the IZa-ChlOIO-Za-iOdide (XXXII) of Example 18 in 3 ml. of acetone is added under nitrogen 0.6 ml. of an aqueous chromous chloride solution (prepared from 5 g. of chromic chloride in 20 ml. of water). The mixture is allowed to remain at room temperature for minutes, after which time water and chloroform are added. The resulting chloroform extract is washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual material crystallizes readily and furnishes pure 12a-chlorocortisone acetate upon recrystallization from 95% alcohol, M.P. about 185;

2: 14,000). The material obtained in this fashion contains some l2a-chloroallopregnane-l7a,2l-diol-3,11,20- trione 21-acetate as shown by the low extinction coeflicient. It is therefore purified by chromatography on acidwashed alumina (1 g.) in the following manner: the substance is dissolved in 3 ml. of benzene and 3 ml. of hexane, poured on the column and eluted at first with benzene (300 ml.) to remove contaminants. Subsequent elution with benzene containing 5% of chloroform yields pure l2a-chlorocortisone acetate of the following properties: M.P. about 195196; [M +82 (c. 1.03 in CHCl A512; 236 m (e=16,800); 5.79 5.88% 6.0214, 6.2011) Analysis.Calcd. for C H O Cl (436.91): C, 63.22; H, 6.69; Cl, 8.11. Found: C, 63.18; H, 6.84; CI, 8.06.

Similarly, 12a-fluoro-2a-iodocortisone 2l-acetate, 12achloro 2a iodo 17a hydroxy 11 ketoprogesterone and 12a fluoro 2a iodo 17a hydroxy 11 ketoprogesterone can be deiodinated to yield l2a-fiuorocortisone 21-acetate (XXVII), l2a-chloro-17a-hydroxy-1lketoprogesterone (XXXVIII) and 12a-fluoro-17a-hydroXy-1l-ketoprogesterone (XXXIX), respectively.

18 EXAMPLE :0

To a solution of 50 mg. of 12a-chlorocortisone acetate (XXXVI) in 3 ml. of methanol is added under nitrogen 0.6 ml. of oxygen free 10% aqueous potassium carbonate. After 30 minutes at room temperature the solution is neutralized with glacial acetic acid and diluted with 3 ml. of water. Crystallization ensued which becomes complete after removal of the methanol in vacuo. The crystals are collected on a filter, washed with water, dried and recrystallized from alcohol.

Similarly, 12u-fiuorocortisone 21-acetate can be hydrolyzed to IZa-fiUOIOCOItiSOllG.

EXAMPLE 21 12a-Chl0r0-A -Pregnadiene-17a,21-Di0l-3,1 1,20- Trione 21-Acetate (XL) A solution of 500 mg. of 12oz-ChlOr0-2a,4adibr0m0- allopregnane-l7a,2l-diol-3,11,20-trione (XXVIII) in 5 ml. of collidine is refluxed for 45 minutes and the result- .ing mixture diluted with chloroform and dilute hydrochloric acid. The resulting chloroform extract is extracted with hydrochloric acid until free of collidine and finally with water. The sodium sulfate dried extract is evaporated in vacuo, dissolved in 2 ml. of chloroform and 8 ml. of benzene and the resulting solution chromatographed on 8 grams of sulfuric acid-washed alumina. The column is first eluted with benzene-chloroform 1:1 (400 ml.) to remove impurities, and then with chloroform (400 ml.). The latter solvent elutes the desired l-dehydro-l2a-chlorocortisone acetate (XL), which is obtained in pure form by crystallization from 95% alcohol.

Similarly, 12 fluoro 2u,4u dibromo allopregnane 1701,21 diol 3,11,20 trione 21 acetate (XXIX), 12a chloro 201,40; dibromo allopregnane 17a ol- 3,1l,20-trione (XXX) and 12a-fluoro-2a,4a-dibromo-allopregnane-17a-ol-3,11,20-trione (XXXI) can be converted to 12a-fiuoro-A -pregnadiene-17a,2l-diol-3,l1, 20-trione 21-acetate (XLI), 12m-chloro-A -pregnadienel7a-ol-3,11,20-trione (XLII), and 12m-fiuoro-A -pregnadiene-17a-ol-3,11,20-trione (XLIII), respectively.

Compounds XL and XLI can then be hydrolyzed to the free 2l-hydroxy steroid by the method of Example 20.

The following examples illustrate one of the processes for converting the ll-keto steroids to their llfl-hydroxy derivatives:

EXAMPLE 22 3,20-Diethylene Ketal of 1 2 ot Chl0r0dortis0ne (XLV) A mixture of 200 mg.-6'f IZa-ChlOIOCOIfiSOIlC (XLIV), 4 ml. of ethylene glycol, 18 ml. of benzene and 15 ml. of p-toluenesulfonic acid monohydrate is refluxed for 5 hours with the aid of a Dean-Stark water separator. After cooling of the reaction mixture, dilute sodium bicarbonate solution is added and the layers are separated. The aqueous phase is extracted with chloroform, the organic phases combined, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The

residue representing 3,20-diethylene ketal of IZa-ChIOlO- cortisone is used in the subsequent reaction of Example 23 without further purification.

EXAMPLE 23 3,20-Diethylene Ketal of 12a-Chl0rohydr0c0rtisone (XLVI) ml. of 3 N sulfuric acid is refluxed for 40 minutes.

. 19 in vacuo. Crystallization of the residue from acetonehexane yields the 3,20-diketal of 12u-chlorohydroc0rtisone (XLVI) in pure form.

EXAMPLE 24 JZu-Chlorohydmcortisone (XLIX) EXAMPLE 25 A PregneHe-I 1 13,1 2fl-0xid0-1 7 :,21 -Di0l-3,20-Diane (XL VII A solution of 400 mg. of the 3,20-ethylene ketal of l2a-chlorohydrocortisone (XLVI) in 10 ml. of methanol and 2 ml. of 10% potassium carbonate in water is refluxed for one hour. The mixture is then neutralized with 3 N aqueous sulfuric acid and when neutral treated with 1.5 ml. of sulfuric acid of the same'strength. After 4 hours at room temperature, chloroform is added and the resulting chloroform extractis washed with dilute sodium bicarbonate and water. Removal of the solvent leaves the l1fl,12fi-oxide (XLVII) as a crystalline residue, which is recrystallized from 95 alcohol.

The 11fl,12fi-oxide (XLVII) is acetylated with pyridineacetic anhydride to form A pregnene-l1p,l2fl-oxido-l7a, 21-diol-3,20-dione ZI-acetate (XLVIII).

EXAMPLE 26 IZa-BrOmohydracortisone Acetate (L) To a solution of 100 mg. of A pregame-113,123- 'oxido-17a,2l-diol-3,20-dione 21-acetate (XLVIII) in ml. of dioxane is added at 0 0.4 ml. of 48% HBr. The mixture is allowed to remain at 0 for one hour and is then diluted with chloroform and water. The chloroform extract is washed with dilute sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is crystallized carefully from 95 alcohol.

EXAMPLE 27' IZa-Br'omocortisone Acetate 12a-bromohydrocortisone acetate (L) is oxidized with chromic acid-sulfuric acid in acetone as describedin Example 2 to yield IZa-bI'OmOCOI'tiSOIIC, acetate.

The invention may be variously otherwise embodied the scope of the appended claims.

We claim:

1. 12a-halo-allopregnane-3p,16p diol 11,20-dione 3- acylate 16-(4-methyl-5-acyloxy)pentanoate, wherein the halo radical has an atomic number less than 35 and wherein the acyl radical is that of a hydrocarbon carboxylic acid of less than ten carbon atoms.

2. 12a-halo-allopregnane -l6a,l7a oxid0-3fl-ol-1L20- dione 3-acylate, wherein the halo radical has an atomic number less than 35 and wherein the acyl radical is that of hydrocarbon carboxylic acid of less than ten carbon atoms.

3. 12a halo-16B- -allopregnane 7 3p,17-diol-l1,20- dione 3-acylate, wherein the l2-halo radical has an atomic number less than 35 and X is a radical selected from the group consisting of 'bromo and iodo and wherein the acyl radical is that of a hydrocarbon carboxylic acid. ofv

less than ten carbon atoms.

4. A 12a,4a-dibromo-12a-halo steroid of the general formula crew 43-0 wherein X is an a-halo radical of atomic number less than 35, and Y' is selected from the group consisting of hydrogen, hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms.

6. A 1lB,12flepoxy steroid selected from the groupconsisting of compounds of the general formula CHQY' 0: Z I o on and the 4,5-dehydro and 1,2;4,5-bisdehydro derivatives thereof, wherein Z' is selected from the group consisting of keto and ketal, and Y is selected from the group consisting of hydrogen, hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms.

7. A process for preparing an ester of l2a-halo-allopregnane-l6a,l7a-oxido-3B-ol-l1,20-dione and a hydrocarbon carboxylic acid of less than ten carbon atoms, which comprises treating the corresponding ester of 12ahalo-allopregnane-3p, l6p-diol-1 1,20-dione 16- (4-methyl-5- acyloxy)pentanoate with hydrogen peroxide in a basic medium, and recovering the resultant product. 7

8. 12a chloroallopregnane-Sfi,l6fi-diol-11,21-dione 3- acetate 16-(4-methyl-5-acetoxy)pentanoate.

9. 12oz chloroallopregnane-l6a,17a-oxido-3fl-ol l1,20- dione 3-acetate.

10. 12 chloro 16p-bromoallopregnane-3/3,17a-diol- 11,20-dione 3-acetate.

11. 12a chloro-l6p-iodoallopregnane-3fi,l7a diol-11, 20-dione 3-acetate.

l2. 12 chl0I'O-2a,4a dibromoallopregnane-17a,21- diol-3,11,20-trione 21-acetate.

13. l2a-chloro-2a-iodocortisone ZI-acetate.

Gould et al.: J=.A.C.S., 74, 3685-3688 (1952). Royals: Advanced Organic Organic Chemistry (1954), 

1. 12A-HALO-ALLOPREGNANE-3B,16B - DIOL - 11,20-DIONE 3ACYLATE 16-(4-METHYL-5-ACYLOXY)PENTANOATE, WHEREIN THE HALO RADICAL HAS AN ATOMIC NUMBER LESS THAN 35 AND WHEREIN THE ACYL RADICAL IS THAT OF A HYDROCARBON CARBOXYLIC ACID OF LESS THAN TEN CARBON ATOMS. 